The overall goal of this grant application is to support the development of a mentored-career that focuses on building a foundation of translational/clinical mechanism-based anticancer drug development. This includes understanding the concept of target validation in the laboratory and drug development in the clinic with emphasis on the use of laboratory-based correlative studies during early phase clinical trials. To achieve this goal, we will focus on the effects of agents targeting the ErbB receptor family on receptor phosphorylation and the activation of downstream PI3K/AKT, MAPK, and JAK/STAT pathways in patients with solid tumors with special emphasis on non-small cell lung cancer (NSCLC). Aim 1: We will determine the prognostic value of EGFR phosphorylation and phosphorylation of downstream effector proteins (p-MAPK, p-AKT, p-STAT3) in comparison to total expression of these proteins in untreated NSCLC. This will be done by performing immunohistochemical analysis of 200 surgically resected NSCLC patients for both total and phosphorylated EGFR, MAPK, AKT and STAT3. Aim 2: To establish whether inhibition of both EGFR and downstream target STAT-3 have additive anti-proliferative activity in vivo. We have established in vitro that the combination of agents targeting EGFR and the JAK/STAT pathways in A431 cells have superior growth inhibitory effects in combination as opposed to single agents. Completion of this aim will demonstrate if strategies to block EGFR and JAK/STAT pathways are more effective than single agents in tumor xenograft models overexpressing EGFR. Aim 3: Determine in a phase I trial if treatment with GW572016, an agent targeting ErbB receptors, decreases EGFPJErbB2 phosphorylation and reduces activation of downstream effector proteins (AKT, MAPK, STAT3) within tumor tissue. Sequential tumor biopsies will be obtained. This trial will establish if this small molecule dual inhibitor of EGFR/erb-B2 effects its target receptor activation and downstream effector proteins in human tumor tissue and it will also establish the optimal biological dose (minimal dose required to effect receptor activation) in patients with advanced solid tumors. Aim 4:To determine the efficacy (response rate) of GW572016 (dual EGFPJErbB2 inhibitor) in NSCLC during a phase II clinical trial. Based on our preclinical data targeting EGFR and ErbB2 results in superior anti-tumor activity as compared to EGFR blockade alone.